RT Journal Article
SR Electronic
T1 Different Effects of Ketoconazole on the Stereoselective First-Pass Metabolism of R/S-Verapamil in the Intestine and the Liver: Important for the Mechanistic Understanding of First-Pass Drug-Drug Interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2186
OP 2196
DO 10.1124/dmd.109.028027
VO 37
IS 11
A1 Helena Anna Thörn
A1 Mikael Hedeland
A1 Ulf Bondesson
A1 Lars Knutson
A1 Mohammed Yasin
A1 Paul Dickinson
A1 Hans Lennernäs
YR 2009
UL http://dmd.aspetjournals.org/content/37/11/2186.abstract
AB In this acute study a pig jejunal intestinal perfusion model with multiple plasma sampling sites and three different administration routes was used to investigate the quantitative contribution of the intestine versus liver to the first-pass extraction of each enantiomer of verapamil (VER). A subclinical dose of ketoconazole (8 mg) was coadministered in the perfusion solution to selectively inhibit gut wall CYP3A. Both enantiomers of VER and its main metabolite norverapamil (NOR) as well as the inhibitor ketoconazole were quantified in all plasma compartments by liquid chromatography-tandem mass spectrometry. The overall first-pass metabolic extraction of VER and the metabolite NOR was shown to be stereoselective with the S-isomer being more extensively extracted. For VER the ratio of R- enantiomer to S-enantiomer was greater in the hepatic vein than in the portal vein (∼2.2 versus 1.4), indicating that the stereoselective metabolism of VER in pigs mainly occurs on the first pass through the liver and not in the intestine. Ketoconazole increased the area under the curve from time 0 to 6 h and Cmax of R- and S-VER at least 3-fold in the portal vein, most likely explained by inhibition of gut wall metabolism. Conversely, hepatic extraction was increased because the effect of gut wall metabolism was not observed at the peripheral sampling sites. In conclusion, this study provided novel and more direct information on the contribution of the intestine and the liver, respectively, to the overall first-pass extraction of racemic VER. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics